CaseFI1: Female, Tunisia, 18 months report

CasePresentingHPOs: HP:0001511, HP:0001508, HP:0001263, HP:0001249, HP:0001337, HP:0000325, HP:0000272, HP:0000303, HP:0000411, HP:0007495, HP:0000518, HP:0000963, HP:0000973, HP:0100678, HP:0012785, HP:0004220, HP:0009162, HP:0010107, HP:0002827, HP:0002808, HP:0001252, HP:0008619, HP:0001629, HP:0001684, HP:0001643, HP:0005301, HP:0003572, HP:0005961, HP:0025082, HP:0030774 (Intrauterine growth retardation, Failure to thrive, Global developmental delay, Intellectual disability, Tremor, Triangular face, Malar flattening, Mandibular prognathia, Protruding ear, Prematurely aged appearance, Cataract, Thin skin, Cutis laxa, Premature skin wrinkling, Flexion contracture of finger, Short middle phalanx of the 5th finger, Absent middle phalanx of 5th finger, Short proximal phalanx of hallux, Hip dislocation, Kyphosis, Muscular hypotonia, Bilateral sensorineural hearing impairment, Ventricular septal defect, Secundum atrial septal defect, Patent ductus arteriosus, Persistent left superior vena cava, Low plasma citrulline, Hypoargininemia, Abnormal cutaneous elastic fiber morphology, Mitochondrial swelling)

HPOsFreeText: Weight: 1770 g (< 3rd percentile); length: 39 cm (< 3rd percentile); OFC: 31 cm (< 3rd percentile); Hand and foot malformations; First metacarpal was bowed bilaterally; Serum Ornithine at 23 μmol/l (ref 21–77), Serum Citrulline at 3 μmol/l (ref 27–43), Serum Arginine at 39 μmol/l (ref 49-129), Serum Proline at 105 μmol/l (ref 71-303), Serum Glutamate at 61 μmol/l (ref 8-64), Serum Aspartate at 8 μmol/l (ref <14)

CaseNotHPOs: HP:0002305, HP:0012443, HP:0009832 (Athetosis, Abnormality of brain morphology, Abnormal distal phalanx morphology of finger)

NotHPOsFreeText: Urinary organic acids, oligosaccharides, purines and pyrimidines were normal

CaseAddInfo: Parents are first-degree cousins, Deletion leads to a frameshift and a premature termination codon

CasePreviousTesting: A skin biopsy was taken and amino acid profiles were analyzed from plasma according to standard procedures

CaseGenotypingMethod: Familial DNA was extracted from peripheral blood samples. Direct sequencing of PYCR1 and exons 2-18 of ALDH18A1 was performed in the affected individual with no result for Exon 15. To confirm if a deletion was responsible, copy number analysis by qPRC was performed with Exon 15 showing a dramatic decrease in signal compared to the others in the affected individual suggesting a homozygous deletion. The parents showed a 50% reduction suggesting a heterozygous phase for the deletion. Different primer combinations allowed for confirmation of the breakpoints with a microdeletion of exon 15 and flanking intronic sequence (1522 bp) with a guanosine insertion.

Variant: NM_002860.4(ALDH18A1):c.1802-2_1924-901del

ClinVar: 156547 https://www.ncbi.nlm.nih.gov/clinvar/variation/156547/

gnomAD: Not in gnomAD

CaseFI2: Male, Turkey, Birth onset

CasePresentingHPOs: HP:0009800, HP:0001195, HP:0000773, HP:0003026, HP:0001650, HP:0003561, HP:0001518, HP:0000252, HP:0004887, HP:0001274, HP:0001250, HP:0000411, HP:0007957, HP:0007495, HP:0000963, HP:0000973, HP:0100678, HP:0010648, HP:0001382, HP:0009815, HP:0001181, HP:0010557, HP:0001374, HP:0012330, HP:0030750, HP:0040187 (Maternal diabetes, Single umbilical artery, Short ribs, Short long bone, Aortic valve stenosis, Birth length less than 3rd percentile, Small for gestational age, Microcephaly, Respiratory failure requiring assisted ventilation, Agenesis of corpus callosum, Seizures, Protruding ear, Corneal opacity, Prematurely aged appearance, Thin skin, Cutis laxa, Premature skin wrinkling, Dermal translucency, Joint hypermobility, Aplasia/hypoplasia of the extremities, Adducted thumb, Overlapping fingers, Congenital hip dislocation, Pyelonephritis, Grade III preterm intraventricular hemorrhage, Neonatal sepsis)

HPOsFreeText: Intrauterine growth restriction birth length: 38 cm (< 3rd percentile), birth weight 1370 g (< 3rd percentile) and microcephaly (OFC at birth was 29.5 cm (3rd–10th percentile)). APGAR scores were 5, 9, and 9 after 1, 5, and 10 min, respectively; Typical facial gestalt

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first-degree cousins that had three healthy daughters and three early abortions

CasePreviousTesting: N/A

CaseGenotypingMethod: Familial DNA was extracted from peripheral blood samples. Direct sequencing of PYCR1 and exons 2-18 of ALDH18A1 was performed in the affected individual with a homozygous single-basepair deletion found predicted to lead to a frameshift and premature stop codon.

Variant: NM_002860.4(ALDH18A1):c.2131del (p.Leu711fs)

ClinVar: 156546 https://www.ncbi.nlm.nih.gov/clinvar/variation/156546/

gnomAD: Not in gnomAD

CaseFZ8: Male, United States, 3 yrs report

CasePresentingHPOs: HP:0001511, HP:0008897, HP:0001999, HP:0000973, HP:0100678, HP:0000963, HP:0010648, HP:0001388, HP:0001374, HP:0001181, HP:0000938, HP:0000270, HP:0025356, HP:0001252, HP:0000518, HP:0000325, HP:0011220, HP:0000337, HP:0000411, HP:0000369, HP:0100790, HP:0005116, HP:0000717, HP:0008872, HP:0000486, HP:0500163, HP:0003572, HP:0500139 (Intrauterine growth retardation, Postnatal growth retardation, Abnormal facial shape, Cutis laxa, Premature skin wrinkling, Thin skin, Dermal translucency, Joint laxity, Congenital hip dislocation, Adducted thumb, Osteopenia, Delayed cranial suture closure, Psychomotor retardation, Muscular hypotonia, Cataract, Triangular face, Prominent forehead, Broad forehead, Protruding ear, Low-set ears, Hernias, Arterial tortuosity, Autism, Feeding difficulties in infancy, Strabismus, Hypoornithinemia, Low plasma citrulline, Hypoprolinemia)

HPOsFreeText: Typical facial gestalt

CaseNotHPOs: HP:0002645, HP:0012443, HP:0001762, HP:0002650, HP:0000252, HP:0001348 (Wormian bones, Abnormality of brain morphology, Talipes equinovarus, Scoliosis, Microcephaly, Brisk reflexes)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo in this case with one other confirmed and one non-confirmed case with the same variant and similar presentation, No family history

CasePreviousTesting: N/A

CaseGenotypingMethod: ALDH18A1 and PYRC1 were investigated by Sanger sequencing, with the latter revealing no abnormalities and the former showing a heterozygous change at the Arg138 residue.Investigation revealed no further variants in the coding regions. Familial sequencing revealed the inheritance was de novo with no variants in the parents.

Variant: NM_002860.4(ALDH18A1):c.413G>A (p.Arg138Gln)

ClinVar: 217260 https://www.ncbi.nlm.nih.gov/clinvar/variation/217260/

gnomAD: Not in gnomAD

CaseFZ2: Male, Finland, 2.9 yrs deceased

CasePresentingHPOs: HP:0001511, HP:0008897, HP:0001999, HP:0000973, HP:0100678, HP:0000963, HP:0010648, HP:0001388, HP:0100790, HP:0001374, HP:0001181, HP:0001762, HP:0002650, HP:0000938, HP:0000270, HP:0002645, HP:0012443, HP:0025356, HP:0008872, HP:0001252, HP:0001348, HP:0000518, HP:0002677, HP:0000325, HP:0011220, HP:0000337, HP:0000411, HP:0000369 (Intrauterine growth retardation, Postnatal growth retardation, Abnormal facial shape, Cutis laxa, Premature skin wrinkling, Thin skin, Dermal translucency, Joint laxity, Hernia, Congenital hip dislocation, Adducted thumb, Talipes equinovarus, Scoliosis, Osteopenia, Delayed cranial suture closure, Wormian bones, Abnormality of brain morphology, Psychomotor retardation, Feeding difficulties in infancy, Muscular hypotonia, Brisk reflexes, Cataract, Small foramen magnum, Triangular face, Prominent forehead, Broad forehead, Protruding ear, Low-set ears)

HPOsFreeText: Typical facial gestalt, Reduced collagen type 1 and 3 production

CaseNotHPOs: HP:0000252, HP:0005116, HP:0000486 (Microcephaly, Arterial tortuosity, Strabismus)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo in this and two other cases with the same variant and similar presentation, No family history,

CasePreviousTesting: N/A

CaseGenotypingMethod: ALDH18A1 and PYRC1 were investigated by Sanger sequencing, with the latter revealing no abnormalities and the former showing a heterozygous change at the Arg138 residue. qPCR was used to exclude the presence of a exonic deletion and investigation revealed no further variants in the coding regions. Familial sequencing revealed the inheritance was de novo with no variants in the parents.

Variant: NM_002860.4(ALDH18A1):c.412C>T (p.Arg138Trp)

ClinVar: 217259 https://www.ncbi.nlm.nih.gov/clinvar/variation/217259/

gnomAD: Not in gnomAD

CaseFZ5: Male, Mexico, 4 yrs report

CasePresentingHPOs: HP:0001511, HP:0008897, HP:0001999, HP:0000973, HP:0100678, HP:0000963, HP:0010648, HP:0001388, HP:0001374, HP:0001181, HP:0001762, HP:0002650, HP:0000938, HP:0000270, HP:0025356, HP:0001252, HP:0001348, HP:0000518, HP:0000325, HP:0011220, HP:0000337, HP:0000411, HP:0000369, HP:0000252 (Intrauterine growth retardation, Postnatal growth retardation, Abnormal facial shape, Cutis laxa, Premature skin wrinkling, Thin skin, Dermal translucency, Joint laxity, Congenital hip dislocation, Adducted thumb, Talipes equinovarus, Scoliosis, Osteopenia, Delayed cranial suture closure, Psychomotor retardation, Muscular hypotonia, Brisk reflexes, Cataract, Triangular face, Prominent forehead, Broad forehead, Protruding ear, Low-set ears, Microcephaly)

HPOsFreeText: Typical facial gestalt

CaseNotHPOs: HP:0005116, HP:0000486, HP:0100790, HP:0002645, HP:0012443 (Arterial tortuosity, Strabismus, Hernias, Wormian bones, Abnormality of brain morphology)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo in this case with one other maternally-confirmed case with the same variant and similar presentation, No family history

CasePreviousTesting: N/A

CaseGenotypingMethod: ALDH18A1 and PYRC1 were investigated by Sanger sequencing, with the latter revealing no abnormalities and the former showing a heterozygous change at the Arg138 residue. qPCR was used to exclude the presence of a exonic deletion and investigation revealed no further variants in the coding regions. Familial sequencing revealed the inheritance was de novo with no variants in the parents.

Variant: NM_002860.4(ALDH18A1):c.413G>T (p.Arg138Leu)

ClinVar: 217261 https://www.ncbi.nlm.nih.gov/clinvar/variation/217261/

gnomAD: Not in gnomAD

FamilyPA2: Italy

FamilyPresentingHPOs: HP:0000519, HP:0002020, HP:0002572, HP:0002313, HP:0003693, HP:0002036, HP:0001761, HP:0003487, HP:0009830, HP:0001288, HP:0001348 (Developmental cataract, Gastroesophageal reflux, Episodic vomiting, Spastic paraparesis, Distal amyotrophy, Hiatus hernia, Pes cavus, Babinski sign, Peripheral neuropathy, Gait disturbance, Brisk reflexes)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: ALDH18A1 was directly sequenced upon investigation for a causal role in SPG9, due to being within the linked region 10q23.3-q24.2, not having been discarded as a candidate gene, and mutations having been known to cause cutis laxa. Previous haplotype analysis also confirmed the linkage to this specific genomic region. This revealed one mutation in each pedigree that strictly co-segregated with the disease. Exome NGS sequencing within the interval showed only two variants were unknown in ExAC with the MYOF substitution unlikely to be disease causing due to poor conservation.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family shows autosomal dominant segregation and haplotyping, Proband is PA2:III-21

FamilyPMIDs: 9973297

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 11

Unaffected: 15

Segregations: 17

pLOD: 4.83

AddSegregationInfo: Candidate gene sequencing

FamilyPA1: United Kingdom

FamilyPresentingHPOs: HP:0000518, HP:0002493, HP:0004322, HP:0001263, HP:0011842, HP:0002013 (Cataract, Upper motor neuron dysfunction, Short stature, Global developmental delay, Abnormality of skeletal morphology, Vomiting)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: ALDH18A1 was directly sequenced upon investigation for a causal role in SPG9, due to being within the linked region 10q23.3-q24.2, not having been discarded as a candidate gene, and mutations having been known to cause cutis laxa. This revealed one mutation in each pedigree that strictly co-segregated with the disease. Exome NGS sequencing within the interval showed only two variants were unknown in ExAC with the MYOF substitution unlikely to be disease causing due to poor conservation.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family shows autosomal dominant segregation

FamilyPMIDs: 8779323

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 7

Unaffected: 3

Segregations: 6

AddSegregationInfo: Candidate Gene Sequencing, Pedigree in Family 1

FamilyFSP410: Italy

FamilyPresentingHPOs: HP:0002064, HP:0002464, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0031993, HP:0500139, HP:0003572, HP:0005961 (Spastic gait, Spastic dysarthria, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Hoffman sign, Hypoprolinemia, Low plasma citrulline, Hypoargininemia)

HPOsFreeText:

FamilyNotHPOs: HP:0001317, HP:0000973, HP:0001999 (Abnormal cerebellum morphology, Cutis laxa, Abnormal facial shape)

NotHPOsFreeText: Cutaneous findings

FamilyGenotypingMethod: Whole genome linkage analysis was performed on the family. Genotypes and exome sequencing was performed on four affected subjects (Patients 6, 8, 25, and 29). Targeted capture was performed and reads were aligned to the human genome. This identified five putatively linked loci with multipoint LOD scores (+1.64 to +1.95) and WES found two missense variants that fits the above criteria and segregates with the disease in ALDH18A1 and PDZD7. Found variants were called and annotated. Segregation in all individuals was checked through Sanger sequencing.

FamilyPreviousTesting: Amino acid levels in Table 4

FamilyAddInfo: Family displays autosomal dominant inheritance

Variant: NM_002860.4(ALDH18A1):c.359T>C (p.Val120Ala)

ClinVar: 217118 https://www.ncbi.nlm.nih.gov/clinvar/variation/217118/

gnomAD: Not in gnomAD

Affected: 9

Unaffected: 6

pLOD: 2.0

AddSegregationInfo: Whole Exome Sequencing, Figure 1 Pedigree

FamilyFSP470: France

FamilyPresentingHPOs: HP:0008969, HP:0002064, HP:0002460, HP:0003701, HP:0002395, HP:0007350, HP:0003487, HP:0031993 (Leg muscle stiffness, Spastic gait, Distal muscle weakness, Proximal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Hoffman sign)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0006938, HP:0001317, HP:0002066, HP:0002464, HP:0100543, HP:0000973 (Impaired vibration sensation at ankles, Abnoral cerebellum morphology, Gait ataxia, Spastic dysarthria, Cognitive impairment, Cutis laxa)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family displays autosomal dominant inheritance

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 4

Unaffected: 5

Segregations: 4

AddSegregationInfo: Whole Exome Sequencing, Figure 1 Pedigree

FamilyFSP856: Portugal

FamilyPresentingHPOs: HP:0001270, HP:0001510, HP:0002317, HP:0002273, HP:0007350, HP:0003487, HP:0003487, HP:0000020, HP:0001249, HP:0002344, HP:0000252, HP:0003700 (Motor delay, Growth delay, Spastic gait, Tetraparesis, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary incontinence, Intellectual disability, Progressive neurologic deterioration, Microcephaly, Generalized amyotrophy)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0002066, HP:0000973 (Gait ataxia, Cutis laxa)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family displays autosomal recessive inheritance, Family is compound heterozygous for these variants

Variant1: NM_002860.4(ALDH18A1):c.1910T>C (p.Leu637Pro)

ClinVar: 217120 https://www.ncbi.nlm.nih.gov/clinvar/variation/217120/

gnomAD: Not in gnomAD

Variant2: NM_002860.4(ALDH18A1):c.383G>A (p.Arg128His)

ClinVar: 217121 https://www.ncbi.nlm.nih.gov/clinvar/variation/217121/

gnomAD: 0.00006533, https://gnomad.broadinstitute.org/variant/10-97397114-C-T

Affected: 4

Unaffected: 13

Segregations: 11

AddSegregationInfo: Whole Exome Sequencing, Figure 1 Pedigree

Case25014: Female, 31 yrs onset, United States

CasePresentingHPOs: HP:0002527, HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0000012, HP:0006938, HP:0100658, HP:0000518, HP:0002322, HP:0010784, HP:0012104, HP:0006913 (Falls, Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary urgency, Impaired vibration sensation at ankles, Cellulitis, Cataract, Resting tremor, Uterine neoplasm, Parietal cortical atrophy, Frontal cortical atrophy)

HPOsFreeText: 5/7 disability score, Chronic microvascular disease

CaseNotHPOs: HP:0001317, HP:0002464, HP:0100543, HP:0000973 (Abnormal cerebellum morphology, Spastic dysarthria, Cognitive impairment, Cutis laxa)

NotHPOsFreeText: N/A

CaseGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

CasePreviousTesting: N/A

CaseAddInfo: Case is sporadic

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

FamilyFSP856: France

FamilyPresentingHPOs: HP:0001263, HP:0002317, HP:0001324, HP:0007350, HP:0003487, HP:0006938, HP:0002066, HP:0002174, HP:0000252, HP:0001999 (Global developmental delay, Spastic gait, Muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Impaired vibration sensation at ankles, Gait ataxia, Postural tremor, Microcephaly, Abnormal facial shape)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0001260, HP:0000973 (Dysarthria, Cutis laxa)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

FamilyPreviousTesting: Normal MRI

FamilyAddInfo: Family displays autosomal recessive inheritance, Family is homozygous for this variant

Variant: NM_002860.4(ALDH18A1):c.2143G>C (p.Asp715His)

ClinVar: 217115 https://www.ncbi.nlm.nih.gov/clinvar/variation/217115/

gnomAD: 0.00002641, https://gnomad.broadinstitute.org/variant/10-97370017-C-G

Affected: 2

Unaffected: 2

Segregations: 4

AddSegregationInfo: Whole Exome Sequencing, Figure 1 Pedigree

FamilyFSP429: France

FamilyPresentingHPOs: HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0031993, HP:0003572, HP:0005961 (Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Hoffman sign, Low plasma citrulline, Hypoargininemia)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0000973, HP:0001999, HP:0100543 (Cutis laxa, Abnormal facial shape, Cognitive impairment)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

FamilyPreviousTesting: Amino acid levels in Table 4

FamilyAddInfo: Family displays autosomal dominant inheritance

Variant: NM_002860.4(ALDH18A1):c.1994G>T (p.Arg665Leu)

ClinVar: 217119 https://www.ncbi.nlm.nih.gov/clinvar/variation/217119/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 7

Segregations: 1

AddSegregationInfo: Candidate gene sequencing, Figure 1 Pedigree

CaseGSHSP44: Female, 44 yrs onset, Australia/UK

CasePresentingHPOs: HP:0040083, HP:0002317, HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0000012, HP:0012104, HP:0006913, HP:0001761, HP:0031520, HP:0006827 (Toe walking, Unsteady gait, Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary urgency, Parietal cortical atrophy, Frontal cortical atrophy, Pes cavus, Groin pain, Atrophy of the spinal cord)

HPOsFreeText: 4/7 disability score, Hip replacement

CaseNotHPOs: HP:0001317, HP:0002464, HP:0100543, HP:0000973, HP:0006938 (Abnormal cerebellum morphology, Spastic dysarthria, Cognitive impairment, Cutis laxa, Impaired vibration sensation at ankles)

NotHPOsFreeText: N/A

CaseGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

CasePreviousTesting: N/A

CaseAddInfo: Case is sporadic

Variant reported as c.1949G>T which does not exist in current transcripts

Variant: NM_002860.3:c.1955C>T (p.Ser652Phe)

CAID: CA377700120 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377700120

gnomAD: Not in gnomAD

CaseBH: Male, Somalia, 8 yrs report

CasePresentingHPOs: HP:0003026, HP:0001511, HP:0000973, HP:0008936, HP:0000023, HP:0008780, HP:0000519, HP:0000639, HP:0011493, HP:0001263, HP:0001999, HP:0000337, HP:0000325, HP:0000494, HP:0000160, HP:0000977, HP:0001181, HP:0002119, HP:0005116 (Short long bone, Intrauterine growth retardation, Cutis laxa, Truncal hypotonia, Inguinal hernia, Congenital bilateral hip dislocation, Developmental cataract, Nystagmus, Central opacification of the cornea, Global developmental delay, Abnormal facial shape, Broad forehead, Triangular face, Downslanted palpebral fissures, Narrow mouth, Soft skin, Adducted thumb, Ventriculomegaly, Arterial tortuosity)

HPOsFreeText: At age 8 years, his height was 96 cm (Z=−5.8) and weight was 11.6 kg (Z=−7.26); Head circumference was 45.4 cm, (Z=−5.0) which is the 50th centile for a 10-month-old boy; Walked with support

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous fourth cousins, Had an older sister and younger brother who were developmentally appropriate and well grown

CasePreviousTesting: N/A

CaseGenotypingMethod: PYCR1 and ALDH18A1 were Sanger sequenced in the proband which revealed a single variant. Chromosomal SNP microarray showed no regions of homozygosity or any other deletions or duplications. Whole Exome Sequencing of genomic DNA from the proband was performed for confirmation again only revealing the single heterozygous missense variant in ALDH18A1. Copy-number analysis was performed and identified no significant variation. Sequencing of the parents revealed a de novo inheritance pattern.

Variant: NM_002860.3:c.377G>A (p.Arg126His)

CAID: CA377706756 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377706756

gnomAD: Not in gnomAD

CaseSK: Male, Pakistan, Birth onset

CasePresentingHPOs: HP:0008846, HP:0001562, HP:0002987, HP:0012453, HP:0001623, HP:0001518, HP:0003561, HP:0002209, HP:0011359, HP:0000963, HP:0100678, HP:0000973, HP:0100679, HP:0000348, HP:0002007, HP:0005280, HP:0000463, HP:0003196, HP:0000430, HP:0000233, HP:0000490, HP:0007759, HP:0000218, HP:0000347, HP:0005328, HP:0002828, HP:0002098, HP:0009110, HP:0000883, HP:0011682, HP:0001655, HP:0100545, HP:0007727, HP:0002033, HP:0002015, HP:0001250, HP:0000023, HP:0001525 (Severe intrauterine growth retardation, Oligohydramnios, Elbow contracture, Bilateral wrist flexion contracture, Breech presentation, Small for gestational age, Birth length less than 3rd percentile, Sparse scalp hair, Dry hair, Thin skin, Wrinkled skin, Cutis laxa, Lack of skin elasticity, High forehead, Frontal bossing, Depressed nasal bridge, Anteverted nares, Short nose, Underdeveloped nasal alae, Thin vermilion border, Deeply set eye, Opacification of the corneal stroma, High-arched palate, Micrognathia, Progeroid facial appearance, Multiple joint contractures, Respiratory distress, Diaphragmatic eventration, Thin ribs, Perimembranous ventricular septal defect, Patent foramen ovale, Arterial stenosis, Opacification of the corneal epithelium, Poor suck, Dysphagia, Seizures, Inguinal hernia, Severe failure to thrive)

HPOsFreeText: Clenched fists, Birth weight was 1.52 kg (<3rd centile), his length was 38 cm (<3rd centile) and his OFC was 29.5 cm (<3rd centile). His Apgar scores were six and nine at 1 and 5 min respectively, Parchment paper‐like textured skin, Prominent cheek jowls, Absent Bowman's membrane, Increased cellularity in the substantia propia, Decreased amount of elastin compared to controls, Less-deefined collagen fibers, Amounts of collagen type I and III were qualitatively decreased

CaseNotHPOs: N/A

NotHPOsFreeText: Normal lung parenchyma

CaseAddInfo: Born to consanguineous first-cousin once removed parents

CasePreviousTesting: Maternal TORCH analysis showed no signs of an acute infection; Amniocentesis showed a normal male karyotype (46,XY), and amniotic fluid virology studies showed no detectable virus; Fetal echocardiography was normal; Fibroblast analysis showed cell proliferation was severely diminished along with abnormally decreased collagen production; A heterozygous variant in PYCR1 was also found (c.329C > T) but is predicted benign and no functional expression alteration of PYCR1 was found.

CaseGenotypingMethod: The exons and exon-intron boundaries of ALDH18A1 were subject to mutation screening via direct sequencing and PCR amplification. A homozygous canonical splice-site variant was found with both parents heterozygous for the same mutation. cDNA was applied to test for functional alteration of the transcript which yielded, rathert than the WT 706 bp protein, a shortened protein ranging from 492-583 bp. These two transcripts either lead to a large deletion of c.1757–1970 or a premature termination codon predicted to undergo NMD.

Variant: NM_002860.4(ALDH18A1):c.1923+1G>A

ClinVar: 29727 https://www.ncbi.nlm.nih.gov/clinvar/variation/29727/

gnomAD: Not in gnomAD